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Siglecs are a family of sialic acid–binding receptors expressed by cells of the immune system and a few other cell types capable of modulating immune cell functions upon recognition of sialoglycan ligands. While human Siglecs primarily bind to sialic acid residues on diverse types of glycoproteins and glycolipids that constitute the sialome, their fine binding specificities for elaborated complex glycan structures and the contribution of the glycoconjugate and protein context for recognition of sialoglycans at the cell surface are not fully elucidated. Here, we generated a library of isogenic human HEK293 cells with combinatorial loss/gain of individual sialyltransferase genes and the introduction of sulfotransferases for display of the human sialome and to dissect Siglec interactions in the natural context of glycoconjugates at the cell surface. We found that Siglec-4/7/15 all have distinct binding preferences for sialylated GalNAc-type O-glycans but exhibit selectivity for patterns of O-glycans as presented on distinct protein sequences. We discovered that the sulfotransferase CHST1 drives sialoglycan binding of Siglec-3/8/7/15 and that sulfation can impact the preferences for binding to O-glycan patterns. In particular, the branched Neu5Acα2–3(6-O-sulfo)Galβ1–4GlcNAc (6′-Su-SLacNAc) epitope was discovered as the binding epitope for Siglec-3 (CD33) implicated in late-onset Alzheimer’s disease. The cell-based display of the human sialome provides a versatile discovery platform that enables dissection of the genetic and biosynthetic basis for the Siglec glycan interactome and other sialic acid–binding proteins.

Legionaminic acids are analogs of sialic acid that occur in several bacteria. The most commonly occurring form is Leg5Ac7Ac, which differs from Neu5Ac only at the C7 (acetamido) and C9 (deoxy) positions. While these differences greatly reduce the susceptibility of Leg compounds to sialidases, several sialyltransferases have been identified that can use CMP-Leg5Ac7Ac as a donor (Watson et al. 2011). We report the successful modification with Leg5Ac7Ac of a glycolipid, GM1a, and two glycoproteins, interferon-α2b and α1-antitrypsin, by means of two mammalian sialyltransferases, namely porcine ST3Gal1 and human ST6Gal1. The Leg5Ac7Ac form of GD1a was not recognized by the myelin-associated glycoprotein (MAG, Siglec-4), confirming the importance of the glycerol moiety in the interaction of sialo-glycans with Siglecs.

While the physical dimensions of climate change are now routinely assessed through multimodel intercomparisons, projected impacts on the global ocean ecosystem generally rely on individual models with a specific set of assumptions. To address these single-model limitations, we present standardized ensemble projections from six global marine ecosystem models forced with two Earth system models and four emission scenarios with and without fishing. We derive average biomass trends and associated uncertainties across the marine food web. Without fishing, mean global animal biomass decreased by 5% (±4% SD) under low emissions and 17% (±11% SD) under high emissions by 2100, with an average 5% decline for every 1 °C of warming. Projected biomass declines were primarily driven by increasing temperature and decreasing primary production, and were more pronounced at higher trophic levels, a process known as trophic amplification. Fishing did not substantially alter the effects of climate change. Considerable regional variation featured strong biomass increases at high latitudes and decreases at middle to low latitudes, with good model agreement on the direction of change but variable magnitude. Uncertainties due to variations in marine ecosystem and Earth system models were similar. Ensemble projections performed well compared with empirical data, emphasizing the benefits of multimodel inference to project future outcomes. Our results indicate that global ocean animal biomass consistently declines with climate change, and that these impacts are amplified at higher trophic levels. Next steps for model development include dynamic scenarios of fishing, cumulative human impacts, and the effects of management measures on future ocean biomass trends.

Model intercomparison studies in the climate and Earth sciences communities have been crucial to building credibility and coherence for future projections. They have quantified variability among models, spurred model development, contrasted within- and among-model uncertainty, assessed model fits to historical data, and provided ensemble projections of future change under specified scenarios. Given the speed and magnitude of anthropogenic change in the marine environment and the consequent effects on food security, biodiversity, marine industries, and society, the time is ripe for similar comparisons among models of fisheries and marine ecosystems. Here, we describe the Fisheries and Marine Ecosystem Model Intercomparison Project protocol version 1.0 (Fish-MIP v1.0), part of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP), which is a cross-sectoral network of climate impact modellers. Given the complexity of the marine ecosystem, this class of models has substantial heterogeneity of purpose, scope, theoretical underpinning, processes considered, parameterizations, resolution (grain size), and spatial extent. This heterogeneity reflects the lack of a unified understanding of the marine ecosystem and implies that the assemblage of all models is more likely to include a greater number of relevant processes than any single model. The current Fish-MIP protocol is designed to allow these heterogeneous models to be forced with common Earth System Model (ESM) Coupled Model Intercomparison Project Phase 5 (CMIP5) outputs under prescribed scenarios for historic (from the 1950s) and future (to 2100) time periods; it will be adapted to CMIP phase 6 (CMIP6) in future iterations. It also describes a standardized set of outputs for each participating Fish-MIP model to produce. This enables the broad characterization of differences between and uncertainties within models and projections when assessing climate and fisheries impacts on marine ecosystems and the services they provide. The systematic generation, collation, and comparison of results from Fish-MIP will inform an understanding of the range of plausible changes in marine ecosystems and improve our capacity to define and convey the strengths and weaknesses of model-based advice on future states of marine ecosystems and fisheries. Ultimately, Fish-MIP represents a step towards bringing together the marine ecosystem modelling community to produce consistent ensemble medium- and long-term projections of marine ecosystems.

An undefined clinical role for HFNCO in bronchiolitis has resulted in variable clinical management--mirroring that seen following the ubiquitous introduction of oxygen-saturation monitoring in the 1980s, which is only now being unraveled.3,4 Elizabeth Kepreotes and colleagues are to be congratulated for bringing the first known randomised controlled trial5 among children of HFNCO compared with standard low-flow nasal cannula oxygen (standard therapy) in acute bronchiolitis--a common condition with no effective treatment and very limited evidence for best practice in standard care.6 Almost unavoidably the trial was open label, and although baseline triage oxygen saturation suggests the study population had relatively mild disease, the subsequent hospital clinical course appears consistent with that seen in many countries: oxygen saturation at baseline frequently falls once children are settled in hospital.7 The trial did not achieve its primary outcome of time to weaning off oxygen--ie, the time from randomisation to the first sustained room-air observation after oxygen.

The TRAPPIST-1 system is the first transiting planet system found orbiting an ultracool dwarf star 1 . At least seven planets similar in radius to Earth were previously found to transit this host star 2 . Subsequently, TRAPPIST-1 was observed as part of the K2 mission and, with these new data, we report the measurement of an 18.77 day orbital period for the outermost transiting planet, TRAPPIST-1 h, which was previously unconstrained. This value matches our theoretical expectations based on Laplace relations 3 and places TRAPPIST-1 h as the seventh member of a complex chain, with three-body resonances linking every member. We find that TRAPPIST-1 h has a radius of 0.752 R ⊕ and an equilibrium temperature of 173 K. We have also measured the rotational period of the star to be 3.3 days and detected a number of flares consistent with a low-activity, middle-aged, late M dwarf. Orbital parameters for the seventh Earth-sized transiting planet around star TRAPPIST-1 are reported, along with an investigation into the complex three-body resonances linking every member of this planetary system.

Lakes play a significant role in the global carbon cycle, acting as sources and sinks of carbon dioxide (CO 2 ). In situ measurements of CO 2 flux (FCO 2 ) from lakes have generally been collected during daylight, despite indications of significant diel variability. This introduces bias when scaling up to whole‐lake annual aquatic carbon budgets. We conducted an international sampling program to ascertain the extent of diel variation in FCO 2 across lakes. We sampled 21 lakes over 41 campaigns and measured FCO 2 at 4‐h intervals over a full diel cycle. Rates of FCO 2 ranged from −3.16 to 4.39 mmol m −2 h −1 . Integrated over a day, FCO 2 ranged from −381.68 to 878.49 mg C m −2 d −1 (mean = 76.54) across campaigns. We identified three characteristic diel patterns in FCO 2 related to trophic status and show that for half of the campaigns, daily flux estimates were biased by > 50% if based on a single (daytime) measurement.

Driver mutations in IDH1 and IDH2 are initiating events in the evolution of chondrosarcoma and several other cancer types. Here, we present evidence that mutant IDH1 is recurrently lost in metastatic central chondrosarcoma. This may reflect either relaxed positive selection for the mutant IDH1 locus, or negative selection for the hypermethylation phenotype later in tumor evolution. This finding highlights the challenge for therapeutic intervention by mutant IDH1 inhibitors in chondrosarcoma.

Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation. Methods Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS. Results A gene based collapsing model showed significant associations with SOD1 , TARDBP , and TBK1 (OR = 19.18, p  = 3.67 × 10 –39 ; OR = 4.73, p  = 2 × 10 –10 ; OR = 2.3, p  = 7.49 × 10 –9 , respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 ( p  = 4.88 × 10 –7 ), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p  = 3.62 × 10 –16 ). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 ( p  = 8.38 × 10 –6 ). Conclusions In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3 . A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2 .

Background Germline CDH1 pathogenic or likely pathogenic variants cause hereditary diffuse gastric cancer (HDGC). Once a genetic cause is identified, stomachs’ and breasts’ surveillance and/or prophylactic surgery is offered to asymptomatic CDH1 carriers, which is life-saving. Herein, we characterized an inherited mechanism responsible for extremely early-onset gastric cancer and atypical HDGC high penetrance. Methods Whole-exome sequencing (WES) re-analysis was performed in an unsolved HDGC family. Accessible chromatin and CDH1 promoter interactors were evaluated in normal stomach by ATAC-seq and 4C-seq, and functional analysis was performed using CRISPR-Cas9, RNA-seq and pathway analysis. Results We identified a germline heterozygous 23 Kb  CDH1 - TANGO6  deletion in a family with eight diffuse gastric cancers, six before age 30. Atypical HDGC high penetrance and young cancer-onset argued towards a role for the deleted region downstream of CDH1 , which we proved to present accessible chromatin, and CDH1 promoter interactors in normal stomach. CRISPR-Cas9 edited cells mimicking the  CDH1 - TANGO6  deletion display the strongest  CDH1  mRNA downregulation, more impacted adhesion-associated, type-I interferon immune-associated and oncogenic signalling pathways, compared to wild-type or  CDH1- deleted cells. This finding solved an 18-year family odyssey and engaged carrier family members in a cancer prevention pathway of care. Conclusion In this work, we demonstrated that regulatory elements lying down-stream of CDH1 are part of a chromatin network that control CDH1 expression and influence cell transcriptome and associated signalling pathways, likely explaining high disease penetrance and very young cancer-onset. This study highlights the importance of incorporating scientific–technological updates and clinical guidelines in routine diagnosis, given their impact in timely genetic diagnosis and disease prevention. Graphical abstract